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At least 307 records · Page 17
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Impact of the HIV-1 genetic background and HIV-1 population size on the evolution of raltegravir resistance

Background Emergence of resistance against integrase inhibitor raltegravir in human immunodeficiency virus type 1 (HIV-1) patients is typically associated with selection of one of three signature mutations: Y143C/R, Q148K/H/R or N155H, representing three distinct resistance pathways. The mechanisms that drive selection of a specific pathway are still poorly understood. We reviewed the effect of the HIV-1 genetic background and population dynamics on the emergence of raltegravir resistance. Using deep sequencing we analyzed the integrase coding sequence (CDS) in longitudinal samples from five patients who initiated raltegravir plus optimized background therapy at viral loads > 5000 copies/ml. To investigate the role of the HIV-1 genetic background we created recombinant viruses containing the viral integrase coding region from pre-raltegravir samples from two patients in whom raltegravir resistance developed through different pathways. The in vitro selections performed with these recombinant viruses were designed to mimic natural population bottlenecks. Results Deep sequencing analysis of the viral integrase CDS revealed that the virological response to raltegravir containing therapy inversely correlated with the relative amount of unique sequence variants that emerged suggesting diversifying selection during drug pressure. In 4/5 patients multiple signature mutations representing different resistance pathways were observed. Interestingly, the resistant population can consist of a single resistant variant that completely dominates the population but also of multiple variants from different resistance pathways that coexist in the viral population. We also found evidence for increased diversification after stronger bottlenecks. In vitro selections with low viral titers, mimicking population bottlenecks, revealed that both recombinant viruses and HXB2 reference virus were able to select mutations from different resistance pathways, although typically only one resistance pathway emerged in each individual culture. Conclusions The generation of a specific raltegravir resistant variant is not predisposed in the genetic background of the viral integrase CDS. Typically, in the early phases of therapy failure the sequence space is explored and multiple resistance pathways emerge and then compete for dominance which frequently results in a switch of the dominant population over time towards the fittest variant or even multiple variants of similar fitness that can coexist in the viral population.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Inhibition of ethylene involved in resistance to E. turcicum in an exotic-derived double haploid maize population

Northern corn leaf blight (NCLB) is an economically important disease of maize. While the genetic architecture of NCLB has been well characterized, the pathogen is known to overcome currently deployed resistance genes, and the role of hormones in resistance to NCLB is an area of active research. The objectives of the study were (i) to identify significant markers associated with resistance to NCLB, (ii) to identify metabolic pathways associated with NCLB resistance, and (iii) to examine role of ethylene in resistance to NCLB. We screened 252 lines from the exotic-derived double haploid BGEM maize population for resistance to NCLB in both field and greenhouse environments. We used a genome wide association study (GWAS) and stepwise regression to identify four markers associated with resistance, followed by a pathway association study tool (PAST) to identify important metabolic pathways associated with disease severity and incubation period. The ethylene synthesis pathway was significant for disease severity and incubation period. We conducted a greenhouse assay in which we inhibited ethylene to examine the role of ethylene in resistance to NCLB. We observed a significant increase in incubation period and a significant decrease in disease severity between plants treated with the ethylene inhibitor and mock-treated plants. Our study confirms the potential of the BGEM population as a source of novel alleles for resistance. We also confirm the role of ethylene in resistance to NCLB and contribute to the growing body of literature on ethylene and disease resistance in monocots.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2017

Hippo effector YAP directly regulates the expression of PD-L1 transcripts in EGFR-TKI-resistant lung adenocarcinoma

Developments of EGFR-TKI and immunotherapy targeting the PD1/PD-L1 pathway are considered most important medical breakthroughs in lung cancer treatment. Nowadays, 3rd generation EGFR TKI is widely used for T790M positive 1st and 2nd EGFR-TKI resistant lung cancer patients. Immunotherapy is powerful option for lung cancer patients without drug targets and chemotherapy resistant patients. It also has changed the concept of conventional anti-cancer therapy in the point of regulating tumor microenvironment. There are many studies linking these two important pathways. Recent studies demonstrated that PD-L1 expression is significantly correlated to the mutation status of EGFR, and activation of EGFR signaling can also induce the expression of PD-L1. However, the real linker between PD-L1 and EGFR signaling remains to be revealed. Our previous study revealed that the Hippo pathway effector YAP confers EGFR-TKI resistance in lung adenocarcinoma, and inhibition of YAP restores sensitivity to EGFR-TKIs. Thus, we examined whether PD-L1 is relevant, in terms of conferring EGFR-TKI resistance and whether YAP directly regulates the expression of PD-L1 in this context. First, we compared the expression levels of PD-L1 and YAP between EGFR-TKI-resistant PC9 cells and the parental PC9 adenocarcinoma cells. The expression levels of both YAP and PD-L1 were markedly higher in the EGFR-TKI-resistant cells compared to the parental cells, suggesting differential expression pattern between two cell types. YAP knockdown significantly decreased the expression of PD-L1 in the EGFR-TKI-resistant cells, while YAP overexpression increased the expression of PD-L1 in the parental PC9 cells. Then, our results revealed that YAP regulates the transcription of PD-L1, and the YAP/TEAD complex binds to the PD-L1 promoter. Surprisingly, knockdown of PD-L1 was sufficient to decrease cell proliferation and wound healing in the EGFR-TKI-resistant PC9 cells. These data suggest a PD1-independent oncogenic function of PD-L1. The Hippo effector YAP plays a crucial role in linking the PD-L1 and EGFR-TKI resistance by directly regulating the expression of PD-L1 in lung cancer. Targeting PD-L1 directly or via YAP could provide an effective therapeutic strategy for EGFR-TKI-resistant lung adenocarcinoma. - Highlights: • PD-L1 expression is elevated in EGFR-TKI-resistant PC9/GR cells compared to that of the parental PC9 cells. • YAP regulates PD-L1 at the transcript level in lung adenocarcinoma. • YAP/PD-L1 signaling regulates cell proliferation and migration independently of T cells and PD1. • The expressions of PD-L1 and YAP are positively correlated in lung adenocarcinoma.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Induction of MEK/ERK activity by AZD8055 confers acquired resistance in neuroblastoma

Highlights: • Prolonged mTOR inhibitor, AZD8055 exposure induced resistance in NB cells. • Resistance against AZD8055 correlated with over-activation of MEK/ERK signaling. • Combination of AZD8055 and U0126 overcome resistance in vitro and in vivo. Mammalian target of rapamycin (mTOR) complex (mTORC) is frequently activated in diverse cancers. Although dual mTORC1/2 inhibitors are currently under development to treat various malignancies, the emergence of drug resistance has proven to be a major complication. AZD8055 is a novel, potent ATP-competitive and specific inhibitor of mTOR kinase activity, which blocks both mTORC1 and mTORC2 activation. In this study, we acquired AZD8055-resistant neuroblastoma (NB) cell sublines by using prolonged stepwise escalation of AZD8055 exposure (4–12 weeks). Here we demonstrate that the AZD8055-resistant sublines (TGW-R and SMS-KAN-R) exhibited marked resistance to AZD8055 compared to the parent cells (TGW and SMS-KAN). The cell cycle G1/S transition was advanced in resistant cells. In addition, the resistance against AZD8055 correlated with over-activation of MEK/ERK signaling pathway. Furthermore, combination of AZD8055 and MEK inhibitor U0126 enhanced the growth inhibition of resistant cells significantly in vitro and in vivo. In conclusion, these data show that targeting mTOR kinase and MEK/ERK signaling simultaneously might help to overcome AZD8055 resistance in NB.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Role of DDX53 in taxol-resistance of cervix cancer cells in vitro

Highlights: • DDX53 is upregulated in taxol-resistance HeLa{sup TR} cervix cancer cells. • DDX53 increases the invasion, migration and colony formation of HeLa{sup TR} cervix cancer cells. • The downregulation of DDX53 contributes to the anti-cancer drug sensitivity of HeLa{sup TR} cervix cancer cells. • DDX53 confers the anti-cancer drug resistance via activation of autophagy in HeLa{sup TR} cervix cancer cells. • DDX53 is upregulated in cancer tissue and tissue-derived cancer cell from patient with glassy cell carcinoma of cervix. Cancer/Testis antigen DDX53 shows high expression level in various tumors and is involved in anti-cancer drug resistance. However, the functional study of DDX53 in cervix cancer remains unknown. In this study, the role of DDX53 in taxol-resistance of cervix cancer cells was investigated. In taxol-resistant Hela{sup TR} cells, DDX53 was significantly increased as compared to the parental HeLa cells. Hela{sup TR} cells also showed upregulation of multidrug resistant gene MDR1, invasive characteristics and decreased apoptosis. In addition, increased autophagy level was observed in Hela{sup TR} cells. Overexpression of DDX53 in HeLa and SiHa markedly led to greater resistance to taxol and cisplatin, whereas knockdown of DDX53 in Hela{sup TR} cells restored sensitivity, demonstrating that DDX53 regulated taxol resistance in cervix cancer cells. DDX53 overexpression in HeLa and SiHa cells enhanced invasion, migration and anchorage independent growth, DDX53 knockdown showed inverse effects in HeLa{sup TR} cells. When DDX53 expression was suppressed by siRNA, autophagic flux and drug resistance of Hela{sup TR} cells were decreased. In addition, DDX53 was upregulated in cervix cancer tissues from patient with a glassy cell carcinoma of cervix. Taken together, these results suggest that DDX53 plays a critical role in taxol-resistance by activating autophagy and a potential therapeutic target for the treatment of taxol-resistant cervix cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

miR-125a-5p regulation increases phosphorylation of FAK that contributes to imatinib resistance in gastrointestinal stromal tumors

Highlights: • Phosphorylation of FAK is regulated by PTPN18 and miR-125a-5p. • pFAK level is higher in imatinib-resistant than imatinib-sensitive GIST882 cells. • FAK inihibitor treatment in imatinib-resistant cells increases imatinib-induced apoptosis. • Blocking FAK phosphorylation rescues miR-125a-5p mediated imatinib resistance. The use of imatinib mesylate has greatly improved the clinical outcome for gastrointestinal stromal tumor (GIST) patients. However, imatinib resistance is still a major clinical challenge, and the molecular mechanisms are not fully understood. We have previously shown that miR-125a-5p and its mRNA target PTPN18 modulate imatinib response in GIST cells. Herein, we evaluated phosphorylated FAK (pFAK) as a candidate downstream target of PTPN18 and the possible association of this regulation with imatinib resistance in GIST. FAK and pFAK expressions were evaluated in GIST882 cells transfected with short hairpin RNA or short interfering RNA targeting PTPN18 or miR-125a-5p mimic, imatinib-resistant GIST882R subclones and clinical samples using Western blot analyses. FAK phosphorylation was blocked using the FAK inhibitor 14 (FAKi) and the effects on cell viability and apoptosis were evaluated using WST-1 assay and cleaved PARP expression. Clinical associations of FAK and pFAK expression with imatinib resistance, KIT mutation and patient outcome were assessed by Fisher's exact test or log-rank test. Over-expression of miR-125a-5p and silencing of PTPN18 increased pFAK, but not FAK, expression in GIST cells. Higher pFAK expression was observed in the GIST882R subclones with acquired imatinib resistance compared to their imatinib-sensitive parental cells. Treatment with FAKi in imatinib-resistant GIST882R cells reduced cell viability and increased apoptosis upon imatinib treatment. Additionally, FAKi could rescue the imatinib resistance effect mediated by miR-125a-5p over-expression. In clinical samples, high FAK and pFAK expressions were associated with KIT mutation status, and high FAK expression was also associated with metastasis in GIST. Higher pFAK was found in cases with shorter overall survival. Our findings highlight an important role for miR-125a-5p regulation and its downstream target pFAK for imatinib resistance in GIST. pFAK and FAK may have prognostic values in GIST.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Integrin α5 mediates intrinsic cisplatin resistance in three-dimensional nasopharyngeal carcinoma spheroids via the inhibition of phosphorylated ERK /caspase-3 induced apoptosis

Highlights: • Highly expressed integrin α5 was observed in in vitro three-dimensional NPC spheroids. • The overexpression of integrin α5 in NPC spheroids demonstrated a correlation with intrinsic cisplatin resistance. • The integrin α5-induced intrinsic cisplatin resistance was mediated by an inactivation of ERK/caspase-3-induced apoptosis. • ATN-161, an integrin α5β1 inhibitor, reduced integrin α5 expression and increased sensitization to cisplatin in NPC spheroids. • ATN-161 reversed the intrinsic cisplatin resistance in NPC spheroids by reactivating ERK/caspase-3-induced apoptosis. Nasopharyngeal carcinoma (NPC) originates in the nasopharynx epithelium. Although concurrent chemoradiation therapy followed by chemotherapy is considered as an effective treatment, there is substantial drug resistance in locally advanced NPC patients. One major contributor to the chemoresistance includes aberrant expression of cell adhesion molecules, such as integrin α and β subunits, giving rise to cell adhesion-mediated drug resistance. Thus, the aim of this study was to investigate the effect of integrin α5 on the development of intrinsic cisplatin resistance in NPC and the associated underlying mechanisms using in vitro three-dimensional (3D) spheroid models, as well as induced cisplatin-resistant NPC (NPCcisR). We demonstrated that established 3D highly- (5-8F) and lowly- (6-10B) metastatic NPC spheroids overexpressed integrin α5 and aggravated their resistance to cisplatin. Besides, enhanced integrin α5 resulted in substantially reduced growth, corresponding to G{sub 0}/G{sub 1} and G{sub 2}/M cell cycle arrest. In addition, 5-8FcisR and 6-10BcisR cells in 3D forms synergistically strengthened endurance of their spheroids to cisplatin treatment as observed by increased resistance index (RI) and decreased apoptosis. Mechanistically, the aberrantly expressed integrin α5 decreased drug susceptibility in NPC spheroids by inactivating ERK and inhibition of caspase-3 inducing apoptosis. Furthermore, the effect of integrin α5 inducing intrinsic resistance was verified via treatment with ATN-161, a peptide inhibitor for integrin α5β1. The results showed dramatic reduction in integrin α5 expression, reversal of ERK phosphorylation and caspase-3 cleavage, together with elevated cisplatin sensitivity, indicating regulation of innate drug resistance via integrin α5. Taken together, our findings suggest that integrin α5 could act as a promising target to enhance the chemotherapeutic sensitivity in NPC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Characterization of micro-contact resistance between a gold nanocrystalline line and a tungsten electrode probe in interconnect fatigue testing

An electromechanically-coupled micro-contact resistance measurement system is built to mimic the contact process during fatigue testing of nanoscale-thickness interconnects using multiple probe methods. The design combines an optical microscope, high-resolution electronic balance, and micromanipulator-controlled electric probe, and is coupled with electrical measurements to investigate microscale contact physics. Experimental measurements are performed to characterize the contact resistance response of the gold nanocrystalline pad of a 35-nm-thick interconnect under mechanical force applied by a tungsten electrode probe. Location of a stable region for the contact resistance and the critical contact force provides better understanding of micro-contact behavior relative to the effects of the contact force and the nature of the contact surface. Increasing contact temperature leads to reduced contact resistance, softens the pad material, and modifies the contact surface. The stability of both contact resistance and interconnect resistance is studied under increasing contact force. Major fluctuations emerge when the contact force is less than the critical contact force, which shows that temporal contact resistance will affect interconnect resistance measurement accuracy, even when using the four-wire method. This performance is demonstrated experimentally by heating the Au line locally with a laser beam. Finally, the contact resistances are calculated using the LET (Li–Etsion–Talke) model together with combined Holm and Sharvin theory under various contact forces. Good agreement between the results is obtained. This research provides a way to measure change in interconnect line resistance directly under a stable contact resistance regime with a two-wire method that will greatly reduce the experimental costs.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗
DOE OSTI2018

Toroidal modelling of resistive internal kink and fishbone instabilities

The influence of energetic particles and plasma resistivity on the n =1 ( n is the toroidal mode number) internal kink and fishbone modes in tokamak plasmas is numerically investigated, using the full toroidal, resistive magnetohydrodynamic-kinetic hybrid stability code MARS-K. The results show that energetic particles can either stabilize or destabilize the ideal internal kink mode, depending on the radial profiles of the particles' density and pressure. Resistive fishbones with and without an ideal wall are investigated. It is found that, in the presence of energetic particles as well as plasma resistivity, two branches of unstable roots exist, for a plasma which is ideally stable to the internal kink instability. One is the resistive internal kink mode. The other is the resistive fishbone mode. These two-branch solutions show similar behaviors, independent of whether the initial ideal kink stability is due to an ideal wall stabilization for high-beta plasmas, or due to a stable equilibrium below the Bussac pressure limit. For a realistic toroidal plasma, the resistive internal kink is the dominant instability, which grows much faster than the resistive fishbone. The plasma resistivity destabilizes the resistive internal kink while stabilizes the resistive fishbone. Systematic comparison with an analytic model qualitatively confirms the MARS-K results. Finally, compared to analytic models based on the perturbative approach, MARS-K offers an improved physics model via self-consistent treatment of coupling between the fluid and kinetic effects due to energetic particles.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
DOE OSTI2024

Molecular and Epidemiological Investigation of Fluconazole-resistant Candida parapsilosis —Georgia, United States, 2021

Abstract Background Reports of fluconazole-resistant Candida parapsilosis bloodstream infections are increasing. We describe a cluster of fluconazole-resistant C parapsilosis bloodstream infections identified in 2021 on routine surveillance by the Georgia Emerging Infections Program in conjunction with the Centers for Disease Control and Prevention. Methods Whole-genome sequencing was used to analyze C parapsilosis bloodstream infections isolates. Epidemiological data were obtained from medical records. A social network analysis was conducted using Georgia Hospital Discharge Data. Results Twenty fluconazole-resistant isolates were identified in 2021, representing the largest proportion (34%) of fluconazole-resistant C parapsilosis bloodstream infections identified in Georgia since surveillance began in 2008. All resistant isolates were closely genetically related and contained the Y132F mutation in the ERG11 gene. Patients with fluconazole-resistant isolates were more likely to have resided at long-term acute care hospitals compared with patients with susceptible isolates (P = .01). There was a trend toward increased mechanical ventilation and prior azole use in patients with fluconazole-resistant isolates. Social network analysis revealed that patients with fluconazole-resistant isolates interfaced with a distinct set of healthcare facilities centered around 2 long-term acute care hospitals compared with patients with susceptible isolates. Conclusions Whole-genome sequencing results showing that fluconazole-resistant C parapsilosis isolates from Georgia surveillance demonstrated low genetic diversity compared with susceptible isolates and their association with a facility network centered around 2 long-term acute care hospitals suggests clonal spread of fluconazole-resistant C parapsilosis. Further studies are needed to better understand the sudden emergence and transmission of fluconazole-resistant C parapsilosis.

Misas, Elizabeth (ORCID:0000000162437716)↗
DOE OSTI2020

Effect of Natural Fermentation of Sorghum on Resistant Starch Molecular Structure and Fermentation Property

Relevant research results have suggested that fermentation can increase the content of sorghum amylose chains and their retrogradation value. Therefore, this study explored the effect of fermentation pretreatment on the yield, digestibility, molecular structure, and in vitro fermentation property of sorghum-resistant starch by conducting fermentation pretreatment of sorghum and extracting the resistant starch from fermented sorghum with pressure-heat compound enzyme method. The results were as follows. After fermentation pretreatment, the yield of sorghum-resistant starch increased, the digestibility of sorghum-resistant starch reduced, the laminated structure size on the surface of the particles became more uniform, and the stacking mode became more neat and denser. The sorghum-resistant starch prepared before and after fermentation did not produce new chemical groups, and its functional group peak remained unchanged. After fermentation, the weight-average molecular weight of sorghum-resistant starch was elevated, and the percentage content of high- and low-molecular substances increased and decreased, respectively, compared with that of the unfermented sorghum-resistant starch. The percentage content of short-chain branches in the branched chain increased, whereas that of the long-chain branches decreased; the crystallinity of sorghum-resistant starch after fermentation decreased, and the intensity of X-diffraction peak changed slightly before and after fermentation. According to the results of the in vitro fermentation experiments, the fermentation broth of sorghum-resistant starch had the highest content of butyric acid and short-chain fatty acid. Research results reveal that, after fermentation pretreatment, sorghum-resistant starch presented increased yield, more complex molecular structure, heavier molecular weight and more uniform surface morphology, more efficient butyric acid generation, and greater fermentation rate than unfermented sorghum-resistant starch.

Ge, YunFei↗
DOE OSTI2016

The Path to High Q-Factors in Superconducting Accelerating Cavities: Flux Expulsion and Surface Resistance Optimization

Accelerating cavities are devices resonating in the radio-frequency (RF) range used to accelerate charged particles in accelerators. Superconducting accelerating cavities are made out of niobium and operate at the liquid helium temperature. Even if superconducting, these resonating structures have some RF driven surface resistance that causes power dissipation. In order to decrease as much as possible the power losses, the cavity quality factor must be increased by decreasing the surface resistance. In this dissertation, the RF surface resistance is analyzed for a large variety of cavities made with different state-of-the-art surface treatments, with the goal of finding the surface treatment capable to return the highest Q-factor values in a cryomodule-like environment. This study analyzes not only the superconducting properties described by the BCS surface resistance, which is the contribution that takes into account dissipation due to quasi-particle excitations, but also the increasing of the surface resistance due to trapped flux. When cavities are cooled down below their critical temperature inside a cryomodule, there is always some remnant magnetic field that may be trapped increasing the global RF surface resistance. This thesis also analyzes how the fraction of external magnetic field, which is actually trapped in the cavity during the cooldown, can be minimized. This study is performed on an elliptical single-cell horizontally cooled cavity, resembling the geometry of cavities cooled in accelerator cryomodules. The horizontal cooldown study reveals that, as in case of the vertical cooldown, when the cooling is performed fast, large thermal gradients are created along the cavity helping magnetic flux expulsion. However, for this geometry the complete magnetic flux expulsion from the cavity equator is more difficult to achieve. This becomes even more challenging in presence of orthogonal magnetic field, that is easily trapped on top of the cavity equator causing temperature rising. The physics behind the magnetic flux expulsion is also analyzed, showing that during a fast cooldown the magnetic field structures, called vortices, tend to move in the same direction of the thermal gradient, from the Meissner state region to the mixed state region, minimizing the Gibbs free energy. On the other hand, during a slow cool down, not only the vortices movement is limited by the absence of thermal gradients, but, also, at the end of the superconducting transition, the magnetic field concentrates along randomly distributed normal-conducting region from which it cannot be expelled anymore. The systematic study of the surface resistance components performed for the different surface treatments, reveals that the BCS surface resistance and the trapped flux surface resistance have opposite trends as a function of the surface impurity content, defined by the mean free path. At medium field value, the BCS surface resistance is minimized for nitrogen-doped cavities and significantly larger for standard niobium cavities. On the other hand, Nitrogen-doped cavities show larger dissipation due to trapped flux. This is consequence of the bell-shaped trend of the trapped flux sensitivity as a function of the mean free path. Such experimental findings allow also a better understanding of the RF dissipation due to trapped flux. The best compromise between all the surface resistance components, taking into account the possibility of trapping some external magnetic field, is given by light nitrogen-doping treatments. However, the beneficial effects of the nitrogen-doping is completely lost when large amount of magnetic field is trapped during the cooldown, underlying the importance of both cooldown and magnetic field shielding optimization in high quality factors cryomodules.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗
NASA NTRS1993

The constant current loop: A new paradigm for resistance signal conditioning

A practical, single, constant-current loop circuit for the signal conditioning of variable-resistance transducers was synthesized, analyzed, and demonstrated. The strain gage and the resistance temperature device are examples of variable-resistance sensors. Lead wires connect variable-resistance sensors to remotely located signal-conditioning hardware. The presence of lead wires in the conventional Wheatstone bridge signal-conditioning circuit introduces undesired effects that reduce the quality of the data from the remote sensors. A practical approach is presented for suppressing essentially all lead wire resistance effects while indicating only the change in resistance value. Theoretical predictions supported by laboratory testing confirm the following features of the approach: (1) the dc response; (2) the electrical output is unaffected by extremely large variations in the resistance of any or all lead wires; (3) the electrical output remains zero for no change in gage resistance; (4) the electrical output is inherently linear with respect to gage resistance change; (5) the sensitivity is double that of a Wheatstone bridge circuit; and (6) the same excitation and sense wires can serve multiple independent gages. An adaptation of the current loop circuit is presented that simultaneously provides an output signal voltage directly proportional to transducer resistance change and provides temperature information that is unaffected by transducer and lead wire resistance variations. These innovations are the subject of NASA patent applications.

Anderson, Karl F.↗
NASA NTRS1994

The constant current loop: A new paradigm for resistance signal conditioning

A practical single constant current loop circuit for the signal conditioning of variable-resistance transducers has been synthesized, analyzed, and demonstrated. The strain gage and the resistance temperature detector are examples of variable-resistance sensors. Lead wires connect variable-resistance sensors to remotely located signal-conditioning hardware. The presence of lead wires in the conventional Wheatstone bridge signal-conditioning circuit introduces undesired effects that reduce the quality of the data from the remote sensors. A practical approach is presented for suppressing essentially all lead wire resistance effects while indicating only the change in resistance value. Theoretical predictions supported by laboratory testing confirm the following features of the approach: (1) dc response; (2) the electrical output is unaffected by extremely large variation in the resistance of any or all lead wires; (3) the electrical output remains zero for no change in gage resistance; (4) the electrical output is inherently linear with respect to gage resistance change; (5) the sensitivity is double that of a Wheatstone bridge circuit; and (6) the same excitation wires can serve multiple independent gages. An adaptation of current loop circuit is presented that simultaneously provides an output signal voltage directly proportional to transducer resistance change and provides temperature information that is unaffected by transducer and lead wire resistance variations. These innovations are the subject of NASA patent applications.

Anderson, Karl F.↗
DOE OSTI2024

Approaching Angstrom-Scale Resolution in Lithography Using Low-Molecular-Mass Resists (<500 Da)

Resists that enable high-throughput and high-resolution patterning are essential in driving the semiconductor technology forward. The ultimate patterning performance of a resist in lithography is limited because of the trade-off between resolution, line-width roughness, and sensitivity; improving one or two of these parameters typically leads to a loss in the third. As the patterned feature sizes approach angstrom scale, the trade-off between these three metrics becomes increasingly hard to resolve and calls for a fundamental rethinking of the resist chemistry. Low-molecular-mass monodispersed metal-containing resists of high atom economy can provide not only very high resolution but also very low line-width roughness without sacrificing sensitivity. Here we describe a modular metal-containing resist platform (molecular mass <500 Da) where a molecular resist consists of just two components: a metal and a radical initiator bonded to it. This simple system not only is amenable to high-resolution electron beam lithography (EBL) and extreme ultraviolet lithography (EUVL) but also unites them mechanistically, giving a consolidated perspective of molecular and chemical processes happening during exposure. Irradiation of the resist leads to the production of secondary electrons that generate radicals in the initiator bonded to metal. This brings about an intramolecular rearrangement and causes solubility switch in the exposed resist. We demonstrate record 1.9–2.0 nm isolated patterns and 7 nm half-pitch dense line-space features over a large area using EBL. With EUVL, 12 nm half-pitch line-space features are shown at a dose of 68 mJ/cm 2 . In both of these patterning techniques, the line-width roughness was found to be ≤2 nm, a record low value for any resist platform, also leading to a low-performance trade-off metric, Z factor, of 0.6 × 10 –8 mJ·nm 3 . With the ultimate resolution limited by instrumental factors, potential patterning at the level of a unit cell can be envisaged, making low-molecular-mass resists best poised for angstrom-scale lithography.

77 NANOSCIENCE AND NANOTECHNOLOGY↗
DOE OSTI2021

NLR diversity and candidate fusiform rust resistance genes in loblolly pine

Resistance to fusiform rust disease in loblolly pine (Pinus taeda) is a classic gene-for-gene system. Early resistance gene mapping in the P. taeda family 10-5 identified RAPD markers for a major fusiform rust resistance gene, Fr1. More recently, single nucleotide polymorphism (SNP) markers associated with resistance were mapped to a full-length gene model in the loblolly pine genome encoding for a nucleotide-binding site leucine-rich repeat (NLR) protein. NLR genes are one of the most abundant gene families in plant genomes and are involved in effector-triggered immunity. Inter- and intraspecies studies of NLR gene diversity and expression have resulted in improved disease resistance. To characterize NLR gene diversity and discover potential resistance genes, we assembled de novo transcriptomes from 92 loblolly genotypes from across the natural range of the species. In these transcriptomes, we identified novel NLR transcripts that are not present in the loblolly pine reference genome and found significant geographic diversity of NLR genes providing evidence of gene family evolution. We designed capture probes for these NLRs to identify and map SNPs that stably cosegregate with resistance to the SC20-21 isolate of Cronartium quercuum f.sp. fusiforme (Cqf) in half-sib progeny of the 10-5 family. We identified 10 SNPs and 2 quantitative trait loci associated with resistance to SC20-21 Cqf. The geographic diversity of NLR genes provides evidence of NLR gene family evolution in loblolly pine. The SNPs associated with rust resistance provide a resource to enhance breeding and deployment of resistant pine seedlings.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Review of metal-containing resists in electron beam lithography: perspectives for extreme ultraviolet patterning

Background: Metal-containing resists entered the mainstream semiconductor industry process flow to mitigate the low absorbance of extreme ultraviolet (EUV) radiation by thin films of organic resists that lead to poor sensitivity and their inability to handle rigors of development and etching conditions. Aim: The long and rich history of using metal-containing resists in electron beam lithography can offer interesting lessons, pointers, and insights to the relatively newcomer EUV lithography, which is slightly over a decade old. Approach: Electron beam lithography has been enjoying a considerable amount of freedom in the choice of resist materials for close to 50 years; especially the use of metal-containing resists to attain not only single digit nanometer resolution, higher sensitivity, and etch resistance but also lower line-edge roughness. Here, we make a comprehensive historical review of the progress made in the patterning of metal-containing resists in electron beam lithography and derive insights that can be potentially useful in EUV patterning. Perspectives: Small molecular weight resists are proven to be crucial for achieving higher resolution with low line-edge roughness. Simplifying process flow by reducing etch-stack-layers is conceivable with metal-containing resists, along with direct-patterning of functional materials for heterogeneous integration. Efficient contact hole patterning at tighter pitches may be incumbent on progress in positive-tone resist research.

77 NANOSCIENCE AND NANOTECHNOLOGY↗
DOE OSTI2019

Insight into the Bacterial Endophytic Communities of Peach Cultivars Related to Crown Gall Disease Resistance

Crown gall disease caused by Agrobacterium tumefaciens severely impacts the production of peach and other fruit trees. Several peach cultivars are partially resistant to A. tumefaciens, but little is known about the roles of endophytic microbiota in disease resistance. In the present study, the endophytic bacterial communities of resistant and susceptible peach cultivars “Honggengansutao” and “Okinawa” were analyzed using universal 16S rRNA gene amplicon sequencing in parallel with the cultivation and characterization of bacterial isolates. A total of 1,357,088 high-quality sequences representing 3,160 distinct operational taxonomic units (OTUs; Proteobacteria, Actinobacteria, Bacteroidetes, and Firmicutes) and 1,200 isolates of 20 genera and 305 distinct ribotypes were collected from peach roots and twigs. It was found that factors including plant developmental stage, cultivar, and A. tumefaciens invasion strongly influenced the peach endophytic communities. The community diversity of endophytic bacteria and the abundance of culturable bacteria were both higher in the roots of the resistant cultivar, particularly after inoculation. Strikingly, the pathogen antagonists Streptomyces and Pseudomonas in roots and Rhizobium in twigs were most frequently detected in resistant plants. Our results suggest that the higher abundance and diversity of endophytic bacteria and increased proportions of antagonistic bacteria might contribute to the natural defense of the resistant cultivar against A. tumefaciens. This work reveals the relationships between endophytic bacteria and disease resistance in peach plants and provides important information for microbiome-based biocontrol of crown gall disease in fruit trees. Agrobacterium tumefaciens as the causal agent of peach crown gall disease can be controlled by planting resistant cultivars. This study profiles the endophytic bacteria in susceptible and resistant peach cultivars, advancing our understanding of the relationships between endophytic bacterial communities and peach crown gall disease, with potential implications for other complex microbiome-plant-pathogen interactions. The resistant cultivar may defend itself by increasing the diversity and abundance of beneficial endophytic bacteria. Finally, the antagonists identified among the genera Streptomyces, Pseudomonas, and Rhizobium may have application potential for biocontrol of crown gall disease in fruit trees.

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